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D. De Ruysscher



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    MO23 - Radiotherapy II: Lung Toxicity, Target Definition and Quality Assurance (ID 107)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      MO23.02 - Quantification of radiation-induced lung damage with CT scans: The possible benefit for radiogenomics (ID 254)

      10:35 - 10:40  |  Author(s): D. De Ruysscher

      • Abstract
      • Presentation
      • Slides

      Background
      Radiation-induced lung damage (RILD) is an important problem. Although physical parameters such as the mean lung dose are used in clinical practice, they are not suited for individualised radiotherapy. As radiosensitivity varies between patients, genetic correlations have been investigated, which appear to be difficult to repeat in validation studies. This may be due, in part, to differences in methods for measuring RILD across studies. Objective, quantitative measurements of RILD on a continuous instead of on an ordinal, semi-quantitative, semi-subjective scale, are needed.

      Methods
      Hounsfield Unit (HU) changes before vs. 3 months post-radiotherapy were correlated per voxel with the radiotherapy dose. Deformable registration was used to register pre and post CT scans and the density increase was quantified for various dose bins. The dose-response curve for increased HU was quantified using the slope of a linear regression (HU/Gy). The end-point for the toxicity analysis was dyspnoea ≥ grade 2.

      Results
      95 lung cancer patients were studied. Radiation dose was linearly correlated with the change in HU (mean R[2]=0.74 ± 0.28). No differences in HU/Gy between groups treated with stereotactic radiotherapy, conventional radiotherapy alone, sequential or concurrent chemo-radiotherapy were observed. In the whole patient group, 33/95 (34.7 %) had dyspnoea ≥ G2. Of the 48 patients with a HU/Gy below the median, 16 (33.3 %) developed dyspnoea ≥ G2, while in the 47 patients with a HU/Gy above the median, 17 (36.1 %) had dyspnoea ≥ G2 (not significant). Individual patients showed a nearly 21-fold difference in radiosensitivity, with HU/Gy ranging from 0 to 10 HU/Gy. Figure 1

      Conclusion
      HU changes identify objectively the whole range of individual radiosensitivity on a continuous, quantitative scale. CT density changes may allow more robust and accurate radiogenomics studies.

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    P2.04 - Poster Session 2 - Tumor Immunology (ID 154)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.04-002 - Differential expression of PD-L1, PD1 and CTLA4 receptor according to histology and tumour vs. surrounding non-malignant lung tissue in non-small cell lung cancer: RNA sequencing data (ID 2427)

      10:30 - 11:30  |  Author(s): D. De Ruysscher

      • Abstract

      Background
      Immune modulatory strategies directed against CTLA4 (Cytotoxic T-Lymphocyte Antigen 4), PD1(Programmed cell Death 1) and PD-L1 (Programmed cell Death 1 Ligand 1) either in monotherapy or in combination with chemotherapy and radiotherapy offer great promise as novel treatments against lung cancer. Its outcome and therapeutic ratio may depend on the expression of the target molecules in tumours and the surrounding non-malignant lung tissue. We here report the expression of CTLA4, PD1 and PD-L1 in primary resected NSCLC and in the surrounding non-malignant lung.

      Methods
      RNA sequencing was performed on tumor tissue and normal lung tissue from resection specimens of NSCLC patients. The association between CTLA4, PD1 and PD-L1 expression levels and histology, gender, age, smoking status (current smoker vs. smoking cessation of at least one year), COPD and CRP blood levels was calculated both in the primary tumour and the normal lung. Results are expressed as mean +/- SD and range. Means were compared using Wilcoxon’s signed rank test for the distributions were non-parametrical. P-values <0.05 were considered significant.

      Results
      Fourteen patients were studied, 11 males and 3 females, with a mean age of 64.6 +/- 10.0 years (41-79). All patients had a smoking history: 6 were current smokers, 8 former smokers. COPD status: 8 no COPD, 1 GOLD class I, 3 GOLD class II, 2 GOLD class III. Pre-operative CRP (mg/dL): 15.0 +/- 2.9 (0.20-54.7). Seven patients had squamous cell cancer, 7 adenocarcinoma. PD-L1 expression in the lung was 3833 +/- 787 (372-5072), PD-L1 in the tumour 2595 +/- 1657 (788-6689), with a tumour/lung ratio of 0.67 +/- 0.37 (0.21-1.32). PD-L1 squamous vs. adenocarcinoma was 1840 +/- 1012 vs. 3350 +/- 1896, p<0.001. PD-L1 in the lung of ex-smokers vs. current smokers: 4136 +/- 811 vs. 3430 ± 591, p<0.001. These associations were not found for CTLA4 and PD1 receptor: CTLA4 tumour squamous vs. adenocarcinoma: 100.9 +/- 46.3 vs. 95.3 +/- 73.6, p=0.86; CTLA4 lung smokers vs. ex-smokers: 78.4 +/- 41.3 vs. 107.0 +/- 75.1, p=0.75. PD1 receptor tumour squamous vs. adenocarcinoma: 591 +/- 244 vs. 689 +/- 263, p=0.31 PD1 receptor in the lung of smokers vs. ex-smokers: 599 +/- 278 vs. 695 +/-216, p=0.46. No associations between CTLA4, PD1 and PD-L1 in the tumour or the lung and gender, age, COPD and CRP blood levels were found.

      Conclusion
      RNA sequencing is a useful method to dissect relevant molecules in the tumour and the lungs. Our results show more PD-L1 expression in adenocarcinoma than in squamous cell cancer, more PD-L1 expression in the non-malignant lung of ex-smokers than in current smokers and reduced PD-L1 in tumours compared to adjacent lung tissue.

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    P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.06-030 - Radiation-induced lung damage quantification with CT scans: Correlation with single nucleotide polymorphisms (ID 2420)

      09:30 - 09:30  |  Author(s): D. De Ruysscher

      • Abstract

      Background
      Radiation-induced lung damage (RILD) is a dose-limiting toxicity of lung radiotherapy. Individual sensitivity can be measured by changes in Hounsfield Units over time (delta HU) on CT scans (De Ruysscher et al. Acta Oncol 2013). This endpoint is specific for lung damage and does not correlate with dyspnoea, which is multi-factorial. In this study, we investigated the association between density changes over time and SNPs aiming at finding individual sensitivity for RILD.

      Methods
      Delta HU/Gy and delta HU/Gy x MLD (Mean Lung Dose), the latter to take into account a volume factor for RILD, were correlated with 314 SNPs related to fibrosis and inflammation. The outcome variables were square root transformed because both were not normally distributed. Univariate ANOVA analyses were performed for comparisons of means. P-values of less than 0.01 were considered to be significant.

      Results
      Eighty-nine lung cancer patients were studied, 63 men and 26 females. Twenty patients were treated with radiotherapy alone, 31 with sequential chemo-RT and 38 with concurrent chemo-RT. Twenty percent of the patients developed grade 2 or more clinical dyspnoea after treatment. Three SNPs were significantly correlated with delta HU/Gy: rs2252070 (p=0.006, MMP13), rs2230588 (p=0.009, JAK1) and rs12901071 (p=0.009, SMAD3) [Table 1A]. For delta HU/Gy x MLD, significant associations were found for rs3819122 (p=0.008, SMAD4), rs2230529 (p=0.009, ITGB2) and rs2230588 (p=0.009, JAK1) [Table 1B]. Figure 1

      Conclusion
      Quantification of CT density changes due to radiotherapy, measured as HU changes over time as a specific and quantitative endpoint for RILD correlates with specific SNPs in genes involved in signal transduction of cytokines (SMAD3/4, JAK1), in the extracellular matrix (MMP13) and in cell adhesion (ITGB2). External validation will follow.